3,4-Methylenedioxymethamphetamine (MDMA;ecstasy) is an amphetamine derivative that has seen an increasing abuse rate over the past two decades, particularly in adolescent and young-adult populations. Both clinical and animal data suggest that there is a high degree of individual variability in the pattern of MDMA use and in the drug's potential for abuse. Thus, the overall goals of the proposed research are to (a) further characterize the individual differences in MDMA-related behaviors that we have observed in rats, (b) determine the specific behaviors that are predictive of subsequent addiction-like behaviors, and (c) determine the neural underpinnings of these individual differences. To do this, we will first run rats in our recently developed behavioral sensitization paradigm in which we manipulate the context of drug administration such that only approximately half of the animals express behavioral sensitization to MDMA. Subsequently, we will determine if individual differences in behavioral sensitization to MDMA are related to addiction-like behaviors in an animal model of relapse. Finally, to begin mapping out the circuitry of relapse to MDMA- seeking behavior, we will combine this behavioral testing with temporary lidocaine inactivation of discrete sub-regions of medial prefrontal cortex, a brain region that appears to be a common anatomical substrate through which a variety of stimuli converge to drive drug-seeking behavior. Results of the proposed study should provide unique insight into the neural mechanisms underlying individual differences in the behavioral effects of MDMA. These types of preclinical investigations into the neurobehavioral traits that are related to addiction-like behaviors are crucial to developing improved treatment strategies for human drug abuse and addiction. PUBLIC HEALTH RELEVANCE: This research will contribute to our understanding of the neural and behavioral traits related to animals'increased vulnerability to addiction-like behaviors. Therefore, the findings may aid in the development of improved treatment options for human drug abuse and addiction.